Age is the major risk factor for cardiovascular diseases (CVD). Two key contributors to the increased risk of CVD in middle-aged and older (MA/O) adults are stiffening of the large elastic arteries and the development of vascular endothelial dysfunction, indicated by impaired nitric oxide (NO)-induced endothelium-dependent dilation (EDD). The mechanisms by which aging causes these physiological changes are incompletely understood, but are believed to involve the development of superoxide-associated oxidative stress. Thus, establishing novel strategies to reduce arterial stiffness and increase vascular endothelial function (EDD) in MA/O adults by reducing oxidative stress is a high biomedical research priority. Trehalose is a safe and naturally occurring carbohydrate with antioxidant effects that is a promising nutraceutical for intervention in the aging process. Recent preclinical findings from our lab indicate that drinking water supplemented with trehalose reduces large elastic artery stiffness, restores NO- mediated EDD, reduces arterial oxidative stress, and reverses age-associated declines in autophagy markers in the aorta of old C57/BL6 mice. However, the effect of trehalose supplementation on vascular function in MA/O adults is entirely unknown. The goal of the present application is to translate these preclinical observations to humans. A pilot study using state-of-the-art research protocols and innovative measurements to determine the efficacy of oral trehalose supplementation for reducing large elastic artery stiffness and improving vascular endothelial function in MA/O adults will be conducted. Hypothesis 1: Oral trehalose therapy will reduce large elastic artery stiffness and increase EDD in MA/O adults without clinical disease, and the improvements will be greater with a longer duration and a higher vs. lower dose. Hypothesis 2: The improvements in vascular function will be associated with evidence consistent with reduced systemic and vascular oxidative stress and may be related to increased vascular autophagic flux. Overall, the proposed research project has the potential to influence clinical practice guidelines by establishing a novel, easy to deliver, cost-effective therapy with antioxidant and autophagy-promoting properties for treating age-associated arterial dysfunction and reducing the risk of CVD with aging.